GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Nora Franceschini; Claudia Giambartolomei; Paul S. de Vries; Chris Finan; Joshua C. Bis; Rachael P. Huntley; Ruth C. Lovering; Salman M. Tajuddin; Thomas W. Winkler; Misa Graff; Maryam Kavousi; Caroline Dale; Albert V. Smith; Edith Hofer; Elisabeth M. van Leeuwen; Ilja M. Nolte; Lingyi Lu; Markus Scholz; Muralidharan Sargurupremraj; Niina Pitkänen; Oscar Franzén; Peter K. Joshi; Raymond Noordam; Riccardo E. Marioni; Shih‐Jen Hwang; Solomon K. Musani; Ulf Schminke; Walter Palmas; Aaron Isaacs; Adolfo Correa; Alan B. Zonderman; Albert Hofman; Alexander Teumer; Amanda J. Cox; André G. Uitterlinden; Andrew Wong; Andries J. Smit; Anne B. Newman; Annie Britton; Arno Ruusalepp; Bengt Sennblad; Bo Hedblad; Bogdan Paşaniuc; Brenda W.J.H. Penninx; Carl D. Langefeld; Christina L. Wassel; Christophe Tzourio; Cristiano Fava; Damiano Baldassarre; Daniel H. O’Leary; Daniel Teupser; Diana Kuh; Elena Tremoli; Elmo Mannarino; Enzo Grossi; E BOERWINKLE; Eric E. Schadt; Erik Ingelsson; Fabrizio Veglia; Fernando Rivadeneira; Frank Beutner; Ganesh Chauhan; Gerardo Heiss; Harold Snieder; Harry Campbell; Henry Völzke; Hugh S. Markus; Ian J. Deary; J. Wouter Jukema; Jacqueline de Graaf; Jacqueline Price; Janne Pott; Jemma C. Hopewell; Jingjing Liang; Joachim Thiery; Jorgen Engmann; Karl Gertow; Kenneth Rice; Kent D. Taylor; Klodian Dhana; Lambertus A. Kiemeney; Lars Lind; Laura M. Raffield; Lenore J. Launer; Lesca M. Holdt; Marcus Dörr; Martin Dichgans; Matthew Traylor; Matthias Sitzer; Meena Kumari; Mika Kivimäki; Mike A. Nalls; Olle Melander; Olli T. Raitakari; Oscar H. Franco; Oscar L. Rueda‐Ochoa; Panos Roussos; Peter H. Whincup; Philippe Amouyel; Philippe Giral; Pramod Anugu; Quenna Wong; Rainer Malik; Rainer Rauramaa; Ralph Burkhardt; Rebecca Hardy; R. Schmidt; Renée de Mutsert; Richard Morris; Rona J. Strawbridge; S. Goya Wannamethee; Sara Hägg; Sonia Shah; Stela McLachlan; Stella Trompet; Sudha Seshadri; Sudhir Kurl; Susan R. Heckbert; Susan M. Ring; Tamara B. Harris; Terho Lehtimäki; Tessel E. Galesloot; Tina Shah; Ulf dé Fairé; Vincent Plagnol; Wayne D. Rosamond; Wendy S. Post; Xiaofeng Zhu; Xiaoling Zhang; Xiuqing Guo; Yasaman Saba; Yukinori Okada; Aniket Mishra; Loes C.A. Rutten‐Jacobs; Anne-Katrin Giese; Sander W. van der Laan; Sólveig Grétarsdóttir; Christopher D. Anderson; Michael Chong; Hieab H.H. Adams; Tetsuro Ago; Peter Almgren; Philippe Amouyel; Hakan Ay; Traci M. Bartz; Oscar Benavente; Steve Bevan; Giorgio B. Boncoraglio; Robert D. Brown; Adam S. Butterworth; Caty Carrera; Cara L. Carty; Daniel I. Chasman; Wei‐Min Chen; John W. Cole; Ioana Cotlarciuc; Carlos Cruchaga; John Danesh; P. Bakker; Anita L. DeStefano; Marcel den Hoed; Qing Duan; Stefan T. Engelter; Guido J. Falcone; Rebecca F. Gottesman; Raji P. Grewal; Stefan Gustafsson; Jeffrey Haessler; Tamara B. Harris; Ahamad Hassan; Aki S. Havulinna; Elizabeth G. Holliday; George Howard; Fang‐Chi Hsu; Hyacinth I. Hyacinth; M. Arfan Ikram; Marguerite R. Irvin; Xueqiu Jian; Jordi Jiménez-Conde; Julie A. Johnson; J. Wouter Jukema; Masahiro Kanai; Keith L. Keene; Brett Kissela; Dawn Kleindorfer; Charles Kooperberg; Michiaki Kubo; Leslie Lange; Carl D. Langefeld; Claudia Langenberg; Jin‐Moo Lee; Robin Lemmens; Didier Leys; Cathryn M. Lewis; Wei‐Yu Lin; Arne Lindgren; Erik Lorentzen; Patrik K. E. Magnusson; Jane Maguire; Ani Manichaikul; Patrick F. McArdle; James F. Meschia; Thomas H. Mosley; Toshiharu Ninomiya; Martin O’Donnell; Sara L. Pulit; Kristiina Rannikmäe; Alex P. Reiner; Kathryn M. Rexrode; Stephen S. Rich; Paul M. Ridker; Natalia S. Rost; Peter M. Rothwell; Tatjana Rundek; Ralph L. Sacco; Saori Sakaue; Michèle M. Sale; Veikko Salomaa; Bishwa R. Sapkota; R. Schmidt; Carsten Oliver Schmidt; Ulf Schminke; Pankaj Sharma; Agnieszka Slowik; Cathie Sudlow; Christian Tanislav; Turgut Tatlisumak; Vincent Thijs; Guðmar Þorleifsson; Unnur Thorsteinsdottir; Steffen Tiedt; Stella Trompet; James Walters; Nicholas J. Wareham; Sylvia Wassertheil‐Smoller; Kerri L. Wiggins; Qiong Yang; Salim Yusuf; Tomi Pastinen; Arno Ruusalepp; Eric E. Schadt; Simon Koplev; Veronica Codoni; Mete Civelek; Nick Smith; David‐Alexandre Trégouët; Ingrid E. Christophersen; Carolina Roselli; Steven A. Lubitz; Patrick T. Ellinor; E Shyong Tai; Jaspal S. Kooner; Norihiro Kato; Jiang He; Pim van der Harst; Paul Elliott; John C. Chambers; Fumihiko Takeuchi; Andrew D. Johnson; Dharambir K. Sanghera; Olle Melander; Christina Jern; Daniel Strbian; Israel Fernández‐Cadenas; W.T. Longstreth; Arndt Rolfs; Jun Hata; Daniel Woo; Jonathan Rosand; Guillaume Paré; Danish Saleheen; Kari Stefansson; Bradford B. Worrall; Steven J. Kittner; Joanna M. M. Howson; Yoichiro Kamatani; Abbas Dehghan; Adrie Seldenrijk; Alanna C. Morrison; Anders Hamsten; Bruce M. Psaty; Cornelia M. van Duijn; Debbie A. Lawlor; Dennis O. Mook‐Kanamori; Donald W. Bowden; Helena Schmidt; James F. Wilson; James G. Wilson; Jerome I. Rotter; Joanna M. Wardlaw; John Deanfield; Julian Halcox; Leo‐Pekka Lyytikäinen; Markus Loeffler; Michele K. Evans; Stéphanie Debette; Steve E. Humphries; Uwe Völker; Vilmundur Guðnason; Aroon D. Hingorani; Johan Björkegren; Juan P. Casas; Christopher J. O’Donnell

doi:10.1038/s41467-018-07340-5

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Nora Franceschini(University of North Carolina at Chapel Hill), Claudia Giambartolomei(University of California, Los Angeles), Paul S. de Vries(The University of Texas Health Science Center at Houston), Chris Finan(University College London), Joshua C. Bis(University of Washington), Rachael P. Huntley(University College London), Ruth C. Lovering(University College London), Salman M. Tajuddin(National Institutes of Health), Thomas W. Winkler(University of Regensburg), Misa Graff(University of North Carolina at Chapel Hill), Maryam Kavousi(Erasmus MC), Caroline Dale(University College London), Albert V. Smith(University of Iceland), Edith Hofer(Medical University of Graz), Elisabeth M. van Leeuwen(Erasmus MC), Ilja M. Nolte(University Medical Center Groningen), Lingyi Lu(Wake Forest University), Markus Scholz(Leipzig University), Muralidharan Sargurupremraj(Université de Bordeaux), Niina Pitkänen(University of Turku), Oscar Franzén(Clinical Gene Networks (Sweden)), Peter K. Joshi(University of Edinburgh), Raymond Noordam(Leiden University Medical Center), Riccardo E. Marioni(Institute of Genetics and Cancer), Shih‐Jen Hwang(National Heart Lung and Blood Institute), Solomon K. Musani(Jackson Memorial Hospital), Ulf Schminke(Universitätsmedizin Greifswald), Walter Palmas(Columbia University), Aaron Isaacs(Maastricht University Medical Centre), Adolfo Correa(Jackson Memorial Hospital), Alan B. Zonderman(National Institutes of Health), Albert Hofman(Harvard University), Alexander Teumer(Universitätsmedizin Greifswald), Amanda J. Cox(Griffith University), André G. Uitterlinden(Erasmus MC), Andrew Wong(MRC Unit for Lifelong Health and Ageing), Andries J. Smit(University Medical Center Groningen), Anne B. Newman(University of Pittsburgh), Annie Britton(University College London), Arno Ruusalepp(Tartu University Hospital), Bengt Sennblad(Uppsala University), Bo Hedblad(Malmö University), Bogdan Paşaniuc(University of California, Los Angeles), Brenda W.J.H. Penninx(Amsterdam Neuroscience), Carl D. Langefeld(Premier Research Group), Christina L. Wassel(Université de Bordeaux), Christophe Tzourio(Université de Bordeaux), Cristiano Fava(University of Verona), Damiano Baldassarre(Tufts University), Daniel H. O’Leary(Tufts University), Daniel Teupser(LMU Klinikum), Diana Kuh(Centro Cardiologico Monzino), Elena Tremoli(University of Milan), Elmo Mannarino(University of Perugia), Enzo Grossi(Centro Diagnostico Italiano), E BOERWINKLE(Baylor College of Medicine), Eric E. Schadt(Cardiovascular Institute of the South), Erik Ingelsson(Uppsala University), Fabrizio Veglia(Erasmus MC), Fernando Rivadeneira(Erasmus MC), Frank Beutner(Université de Bordeaux), Ganesh Chauhan(University of North Carolina at Chapel Hill), Gerardo Heiss(University of North Carolina at Chapel Hill), Harold Snieder(University Medical Center Groningen), Harry Campbell(Universitätsmedizin Greifswald), Henry Völzke(University of Cambridge), Hugh S. Markus(University of Cambridge), Ian J. Deary(Leiden University Medical Center), J. Wouter Jukema(Radboud University Nijmegen), Jacqueline de Graaf(Radboud University Nijmegen), Jacqueline Price(University of Edinburgh), Janne Pott(University of Oxford), Jemma C. Hopewell(University of Oxford), Jingjing Liang(Case Western Reserve University), Joachim Thiery(University College London), Jorgen Engmann(Karolinska Institutet), Karl Gertow(University of Washington), Kenneth Rice(The Lundquist Institute), Kent D. Taylor(Rush University Medical Center), Klodian Dhana(Rush University Medical Center), Lambertus A. Kiemeney(Uppsala University), Lars Lind(University of North Carolina at Chapel Hill), Laura M. Raffield(University of North Carolina at Chapel Hill), Lenore J. Launer(National Institutes of Health), Lesca M. Holdt(LMU Klinikum), Marcus Dörr(Universitätsmedizin Greifswald), Martin Dichgans(University of Cambridge), Matthew Traylor(Goethe University Frankfurt), Matthias Sitzer(Goethe University Frankfurt), Meena Kumari(University of Essex), Mika Kivimäki(National Institutes of Health), Mike A. Nalls(National Institutes of Health), Olle Melander(University of Turku), Olli T. Raitakari(University of Turku), Oscar H. Franco(University of Bern), Oscar L. Rueda‐Ochoa(Industrial University of Santander), Panos Roussos(Allen Institute for Brain Science), Peter H. Whincup(Inserm), Philippe Amouyel(Inserm), Philippe Giral(Jackson Memorial Hospital), Pramod Anugu(University of Washington), Quenna Wong(University of Washington), Rainer Malik(Kuopio University Hospital), Rainer Rauramaa(Kuopio University Hospital), Ralph Burkhardt(University Hospital Regensburg), Rebecca Hardy(Medical University of Graz), R. Schmidt(Medical University of Graz), Renée de Mutsert(Leiden University Medical Center), Richard Morris(Karolinska Institutet), Rona J. Strawbridge(Karolinska Institutet), S. Goya Wannamethee(Karolinska Institutet), Sara Hägg(Karolinska Institutet), Sonia Shah(University College London), Stela McLachlan(Leiden University Medical Center), Stella Trompet(Boston University), Sudha Seshadri(Boston University), Sudhir Kurl(Kaiser Permanente Washington Health Research Institute), Susan R. Heckbert(Kaiser Permanente Washington Health Research Institute), Susan M. Ring(National Institutes of Health), Tamara B. Harris(National Institutes of Health), Terho Lehtimäki(Radboud University Nijmegen), Tessel E. Galesloot(Radboud University Nijmegen), Tina Shah(Karolinska University Hospital), Ulf dé Fairé(Karolinska University Hospital), Vincent Plagnol(University of North Carolina at Chapel Hill), Wayne D. Rosamond(University of North Carolina at Chapel Hill), Wendy S. Post(Johns Hopkins University), Xiaofeng Zhu(National Heart Lung and Blood Institute), Xiaoling Zhang(Boston University), Xiuqing Guo(The Lundquist Institute), Yasaman Saba(Medical University of Graz), Yukinori Okada(Université de Bordeaux), Aniket Mishra(Université de Bordeaux), Loes C.A. Rutten‐Jacobs(Harvard University), Anne-Katrin Giese(Harvard University), Sander W. van der Laan(deCODE Genetics (Iceland)), Sólveig Grétarsdóttir(deCODE Genetics (Iceland)), Christopher D. Anderson(Broad Institute), Michael Chong(Erasmus MC), Hieab H.H. Adams(Kyushu University), Tetsuro Ago(Kyushu University), Peter Almgren(Inserm), Philippe Amouyel(Inserm), Hakan Ay(University of Washington), Traci M. Bartz(University of British Columbia), Oscar Benavente(University of British Columbia), Steve Bevan(Fondazione IRCCS Istituto Neurologico Carlo Besta), Giorgio B. Boncoraglio(Mayo Clinic), Robert D. Brown(Mayo Clinic), Adam S. Butterworth(Universitat Autònoma de Barcelona), Caty Carrera(Universitat Autònoma de Barcelona), Cara L. Carty(Children's National), Daniel I. Chasman(Brigham and Women's Hospital), Wei‐Min Chen(University of Maryland, Baltimore), John W. Cole(University of Maryland, Baltimore), Ioana Cotlarciuc(Royal Holloway University of London), Carlos Cruchaga(Washington University in St. Louis), John Danesh(University of Cambridge), P. Bakker(University Medical Center Utrecht), Anita L. DeStefano(Boston University), Marcel den Hoed(Uppsala University), Qing Duan(University of Cambridge), Stefan T. Engelter(Broad Institute), Guido J. Falcone(Broad Institute), Rebecca F. Gottesman(Johns Hopkins University), Raji P. Grewal(Uppsala University), Stefan Gustafsson(Uppsala University), Jeffrey Haessler(National Institutes of Health), Tamara B. Harris(Leeds General Infirmary), Ahamad Hassan(Leeds General Infirmary), Aki S. Havulinna(Finnish Institute for Health and Welfare), Elizabeth G. Holliday(University of Alabama at Birmingham), George Howard(University of Alabama at Birmingham), Fang‐Chi Hsu(Emory University), Hyacinth I. Hyacinth(Emory University), M. Arfan Ikram(Erasmus MC), Marguerite R. Irvin(University of Alabama at Birmingham), Xueqiu Jian(Universitat Autònoma de Barcelona), Jordi Jiménez-Conde(Universitat Autònoma de Barcelona), Julie A. Johnson(Leiden University Medical Center), J. Wouter Jukema(University of California, Los Angeles), Masahiro Kanai(University of California, Los Angeles), Keith L. Keene(East Carolina University), Brett Kissela(University of Cincinnati Medical Center), Dawn Kleindorfer(Fred Hutch Cancer Center), Charles Kooperberg(Fred Hutch Cancer Center), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Leslie Lange(Wake Forest University), Carl D. Langefeld(University of Cambridge), Claudia Langenberg(Washington University in St. Louis), Jin‐Moo Lee(Washington University in St. Louis), Robin Lemmens(Inserm), Didier Leys(Inserm), Cathryn M. Lewis(King's College London), Wei‐Yu Lin(Lund University), Arne Lindgren(Lund University), Erik Lorentzen(Karolinska Institutet), Patrik K. E. Magnusson(University of Technology Sydney), Jane Maguire(University of Technology Sydney), Ani Manichaikul(University of Maryland, Baltimore), Patrick F. McArdle(University of Maryland, Baltimore), James F. Meschia(Jackson Memorial Hospital), Thomas H. Mosley(Kyushu University), Toshiharu Ninomiya(Kyushu University), Martin O’Donnell(Ollscoil na Gaillimhe – University of Galway), Sara L. Pulit(University Medical Center Utrecht), Kristiina Rannikmäe(Fred Hutch Cancer Center), Alex P. Reiner(Brigham and Women's Hospital), Kathryn M. Rexrode(Brigham and Women's Hospital), Stephen S. Rich(Harvard University), Paul M. Ridker(Brigham and Women's Hospital), Natalia S. Rost(Harvard University), Peter M. Rothwell(University of Miami), Tatjana Rundek(University of Miami), Ralph L. Sacco(University of Miami), Saori Sakaue(University of Virginia), Michèle M. Sale(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Institute for Health and Welfare), Bishwa R. Sapkota(Medical University of Graz), R. Schmidt(Medical University of Graz), Carsten Oliver Schmidt(Universitätsmedizin Greifswald), Ulf Schminke(Royal Holloway University of London), Pankaj Sharma(Jagiellonian University), Agnieszka Slowik(Jagiellonian University), Cathie Sudlow(Justus-Liebig-Universität Gießen), Christian Tanislav(Justus-Liebig-Universität Gießen), Turgut Tatlisumak(Florey Institute of Neuroscience and Mental Health), Vincent Thijs(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Unnur Thorsteinsdottir(deCODE Genetics (Iceland)), Steffen Tiedt(Leiden University Medical Center), Stella Trompet(Leiden University Medical Center), James Walters(University of Cambridge), Nicholas J. Wareham(Albert Einstein College of Medicine), Sylvia Wassertheil‐Smoller(Albert Einstein College of Medicine), Kerri L. Wiggins(Boston University), Qiong Yang(Boston University), Salim Yusuf(Population Health Research Institute), Tomi Pastinen(Tartu University Hospital), Arno Ruusalepp(Tartu University Hospital), Eric E. Schadt(Clinical Gene Networks (Sweden)), Simon Koplev(Inserm), Veronica Codoni(Inserm), Mete Civelek(VA Office of Research and Development), Nick Smith(Kaiser Permanente Washington Health Research Institute), David‐Alexandre Trégouët(Broad Institute), Ingrid E. Christophersen(Broad Institute), Carolina Roselli(Broad Institute), Steven A. Lubitz(Broad Institute), Patrick T. Ellinor(Broad Institute), E Shyong Tai(National University of Singapore), Jaspal S. Kooner(National Center for Global Health and Medicine), Norihiro Kato(Tulane University), Jiang He(Tulane University), Pim van der Harst(University Medical Center Groningen), Paul Elliott(MRC Centre for Environment and Health), John C. Chambers(Ealing Hospital), Fumihiko Takeuchi(National Center for Global Health and Medicine), Andrew D. Johnson(National Heart Lung and Blood Institute), Dharambir K. Sanghera(Malmö University), Olle Melander(Malmö University), Christina Jern(University of Helsinki), Daniel Strbian(Universitat Autònoma de Barcelona), Israel Fernández‐Cadenas(Universitat Autònoma de Barcelona), W.T. Longstreth(University of Washington), Arndt Rolfs(Kyushu University), Jun Hata(Kyushu University), Daniel Woo(Broad Institute), Jonathan Rosand(Broad Institute), Guillaume Paré(Population Health Research Institute), Danish Saleheen(deCODE Genetics (Iceland)), Kari Stefansson(deCODE Genetics (Iceland)), Bradford B. Worrall(University of Maryland, Baltimore), Steven J. Kittner(University of Maryland, Baltimore), Joanna M. M. Howson(University of Cambridge), Yoichiro Kamatani(Kyoto University), Abbas Dehghan(Erasmus MC), Adrie Seldenrijk(GGZ inGeest), Alanna C. Morrison(Karolinska Institutet), Anders Hamsten(University of Washington), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Cornelia M. van Duijn(Erasmus MC), Debbie A. Lawlor(Leiden University Medical Center), Dennis O. Mook‐Kanamori(Leiden University Medical Center), Donald W. Bowden(Medical University of Graz), Helena Schmidt(Medical University of Graz), James F. Wilson(Western General Hospital), James G. Wilson(The Lundquist Institute), Jerome I. Rotter(The Lundquist Institute), Joanna M. Wardlaw(UK Dementia Research Institute), John Deanfield(Swansea University), Julian Halcox(Tampere University), Leo‐Pekka Lyytikäinen(Tampere University), Markus Loeffler(National Institutes of Health), Michele K. Evans(National Institutes of Health), Stéphanie Debette(Université de Bordeaux), Steve E. Humphries(Universitätsmedizin Greifswald), Uwe Völker(University of Iceland), Vilmundur Guðnason(University of Iceland), Aroon D. Hingorani(Karolinska University Hospital), Johan Björkegren(Karolinska University Hospital), Juan P. Casas(Harvard University), Christopher J. O’Donnell(VA Boston Healthcare System)

Nature Communications

November 27, 2018

10.1038/s41467-018-07340-5

Cited by 177Open Access

Full Text

Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

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